Effects of digital cognitive behavioral therapy for depression on suicidal thoughts and behavior: Protocol for a systematic review and meta-analysis of individual participant data

Introduction Digital cognitive behavioral therapy (i-CBT) interventions for the treatment of depression have been extensively studied and shown to be effective in the reduction of depressive symptoms. However, little is known about their effects on suicidal thoughts and behaviors (STB). Information on the impact of digital interventions on STB are essential for patients’ safety because most digital interventions are self-help interventions without direct support options in case of a suicidal crisis. Therefore, we aim to conduct a meta-analysis of individual participant data (IPDMA) to investigate the effects of i-CBT interventions for depression on STB and to explore potential effect moderators. Methods Data will be retrieved from an established and annually updated IPD database of randomized controlled trials investigating the effectiveness of i-CBT interventions for depression in adults and adolescents. We will conduct a one-stage and a two-stage IPDMA on the effects of these interventions on STB. All types of control conditions are eligible. STB can be measured using specific scales (e.g., Beck scale suicide, BSS) or single items from depression scales (e.g., item 9 of the PHQ-9) or standardized clinical interviews. Multilevel linear regression will be used for specific scales, and multilevel logistic regression will be used for treatment response or deterioration, operationalized as a change in score by at least one quartile from baseline. Exploratory moderator analyses will be conducted at participant, study, and intervention level. Two independent reviewers will assess the risk of bias using the Cochrane Risk of Bias Tool 2. Conclusion This IPDMA will harness the available data to assess the effects (response and deterioration) of i-CBT interventions for depression interventions on STB. Information about changes in STB is essential to estimate patients’ safety when engaging in digital treatment formats. Trial registration We will pre-register this study with the open science framework after article acceptance to ensure consistency between online registration and the published trial protocol.


Introduction
Digital interventions for the treatment of depression have been extensively studied and shown to be effective in the reduction of depressive symptoms. However, little is known about their effects on suicidal thoughts and behaviors (STB). Information on the impact of digital interventions on STB are essential for patients' safety because most digital interventions are built as self-help interventions without direct support options in case of a suicidal crisis. We, therefore, aim to conduct a meta-analysis of individual participant data (IPD) to investigate the effects of digital depression interventions on STB and to explore potential effect moderators. Methods Data will be retrieved from an established and annually updated IPD database of randomized controlled trials investigating the effectiveness of digital cognitive behavior therapy interventions for depression in adults and adolescents. We will conduct a onestage and a two-stage IPDMA on the effects of these interventions on STB. All types of control conditions are eligible. STB can be measured with specific scales (e.g., Beck scale suicide, BSS) or single items from depression scales (e.g., item 9 of the PHQ-9) or standardized clinical interviews. Multilevel linear regression will be used for specific scales, and multilevel logistic regression will be used for treatment response or deterioration, which will be operationalized as a change in score by at least one quartile from baseline. Moderator analyses will be conducted at the participant-, study-, and intervention-level. Two independent reviewers will assess the risk of bias using the Cochrane Risk of Bias Tool 2. Conclusion This IPD meta-analysis will harness the available data to assess the effects (response and deterioration) of digital depression interventions on STB. Information about changes in STB is essential to estimate patients'safety when engaging in digital treatment formats.  Have or will the sponsors or funders play any role in the study design, data collection (when applicable) and analysis, decision to publish, or preparation of the manuscript?
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If the manuscript reports pilot data • The analysis R codes will be made available online at OSF with publication. Individual participant data cannot be provided due to confidenciality agreements.

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Additional data availability information: Tick here if the URLs/accession numbers/DOIs will be available only after acceptance of the manuscript for publication so that we can ensure their inclusion before publication. items from depression scales (e.g., item 9 of the PHQ-9) or standardized clinical interviews. 41 Multilevel linear regression will be used for specific scales, and multilevel logistic regression 42 will be used for treatment response or deterioration, which will be operationalized as a change 43 in score by at least one quartile from baseline. Moderator analyses will be conducted at the 44 participant-, study-, and intervention-level. Two independent reviewers will assess the risk of 45 bias using the Cochrane Risk of Bias Tool 2. psychotherapy are effective in the treatment of depression [2][3][4][5][6]. Psychotherapy is also the 67 preferred first line treatment option by many patients [7,8] and outperforms medication 68 treatment in terms of side effects and long-term effectiveness [9][10][11]. However, the scalability 69 of psychotherapy is limited due to several barriers, including high treatment costs, low 70 availability of trained clinicians and stigma [12][13][14]. Therefore, the development of new 71 treatment approaches and scalable formats is an urgent priority.

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To meet this challenge, extensive research efforts have been conducted into digital behavioral 73 interventions over recent decades [15,16]

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This study is pre-registered with OSF (Note: We will pre-register this study with the open 136 science framework after article acceptance to ensure consistency between online registration 137 and the published trial protocol.) and is reported according to the PRISMA protocols 138 statement [40]. The review will be reported according to the PRISMA IPD guideline [41]. We 139 will report potential amendments to the protocol in the final report. synchronous or asynchronous). We will exclude interventions that specifically target suicidal 148 ideation; however, we will not exclude interventions that exclusively apply safety procedures 149 or provide emergency contacts. Blended care, i.e., internet-based interventions combined 150 with face-to-face treatment, will be excluded. Study identification and data extraction 164 We will use an already-existing database for RCTs investigating psychological interventions for 165 depression that has been described in detail elsewhere [20,38,39]. The database is updated on 166 an annual basis. IPD were sought regardless of whether the published articles reported the 167 assessment of STB. We will extract deidentified IPD from all randomized participants, as well 168 as relevant data items from published articles, including study identification items, study 169 procedures, and aggregated clinical, and sociodemographic participant data. This will include 170 data on the theoretical foundation of the intervention, delivery mode of content, amount of 171 human support in remote treatments, and qualification of healthcare providers.

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The primary outcome of this study will be the effects of the interventions on STB assessed by 173 specific scales (e.g., Beck Scale for Suicide Ideation [46]), single item analysis from depression 174 scales, or standardized interviews (e.g., suicidality item of the HAMD). Where available, we 175 will use both specific scales and single items in separate analyses. If there are multiple 176 validated measures of STB, we will prefer self-reports over clinician ratings, as individuals are 177 potentially more likely to report existing STB in self-report [47,48] incorporating the participant's perspective (also in clinician-rated outcomes), and blinding is 188 rarely possible in psychotherapy research. By excluding these items from the evaluation, we In the analyses, we will use all available data to provide an estimation of the effect on STB. We 222 will conduct sensitivity analyses to check for the robustness of results. In addition, we will 223 analyze STB in three indices: (1) a continuous score for the studies providing validated 224 questionnaires for STB, (2) treatment response and (3)  potential to reach a one-point change might be different, which is why we will conduct 231 sensitivity analyses for each measuring instrument (see sensitivity analyses below). All 232 analyses will be conducted using R.

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One-stage IPDMA 234 We will perform a one-stage IPDMA where all available IPD is merged in a hierarchical model, 235 with participants nested in trials. This allows more sophisticated analyses compared to two-236 stage approaches where estimates are calculated for each study separately in a first step [50], 237 and then pooled in a second step. Importantly, the one-stage approach allows fine-grained 238 moderator analyses [51]. We will model a random intercept in each of the models, reflecting 239 the hierarchical structure of the data. The treatment effect may be modeled as fixed or 240 random (for a homogenous or heterogenous treatment effect, respectively); the model will 241 be chosen based on model comparisons. 242 We will perform a multilevel linear regression to investigate the effects on severity of STB. 243 This analysis will be conducted with the subgroup of studies providing a continuous measure 244 for STB. We will shift the scores to the same scale starting point and scale the post-245 intervention scores to the study-specific variance to ensure that scales are comparable across 246 studies. In addition, we will control for baseline STB. We will exclude all participants that did 247 not report STB at baseline from this analysis. 248 For the analyses of treatment response, we will conduct a multilevel logistic regression 249 (response vs. no response). For this analysis, we will use single-item measures; this will also 250 be the case for studies that additionally provide a full measure of STB to increase 251 comparability across trials. We will exclude all participants that reported no baseline STB at 252 baseline. Response will be defined as STB reduction of at least one point in the item at post-253 intervention.

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For the analyses of symptom deterioration, we will conduct a multilevel logistic regression 255 (deterioration vs. no deterioration), analogous to the analysis of treatment response. Thus, 256 we will use single-item measures from all available studies. We will define deterioration as at 257 least a one-point deterioration in the respective item from baseline to post-intervention per 258 participant. Participants who report the maximum score in STB at baseline will be excluded 259 from the analysis because they cannot show deterioration. 260 Furthermore, if feasible, we will investigate the effects on suicidal behavior using logistic 261 multilevel regression. For this outcome, we will combine both suicide attempts and deaths to 262 a binary outcome (i.e., either at least one suicide attempt during the intervention period, or 263 no suicide attempt).

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Two-stage IPDMA 265 In addition, we will perform two-stage IPDMAs to analyze the IPD separately in each study and 266 then combine the estimates to calculate the pooled effect sizes. We will conduct a separate 267 two-stage IPDMA for all three indices of STB. Thus, we will calculate Hedges' g for the severity 268 of STB, as well as the log odds ratios of treatment response and symptom deterioration. Based 269 on the analysis of treatment response, we will calculate the number-needed-to-treat (NNT).

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This procedure will allow for comparisons of the proposed IPDMA with prior and future meta-271 analyses. We will investigate between-study heterogeneity using I2. analyses will focus on single items extracted from depression scales (e.g., item 9 of the PHQ-307 9). This reduces the degree of granulation, as well as increasing the error of the effect size 308 estimation, and consequently reduces the content validity. Secondly, individuals who report 309 elevated STB at baseline are often excluded from randomized clinical trials [27], which reduces 310 the baseline symptom severity in the study population and therefore leaves less room for 311 improvement compared to trials where STB are the primary outcome. Additionally, we will 312 exclude people without STB at baseline from our response analysis, further reducing the total 313 number of individuals in the planned analysis. 314 Despite these limitations, this IPDMA is the first meta-analytic investigation to analyze the 315 effects of digital depression interventions on STB in most available trials. The results of this 316 study will provide invaluable insights into the benefits and risks of delivering digital 317 interventions for people who experience suicidal thoughts in the context of depression. The authors have declared that no competing interests exist. 329

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LBS is the overall guarantor of this research protocol and takes responsibility for the content. LBS 331 designed the trial and acquired funding together with HB. LBS acquired ethics approval, is the chief 332 investigator of the trial, coordinates the trial management and wrote and revised the manuscript. RB, 333 MB and PD made major contributions to methodological aspects. EK and PC will provide access to the 334 IPD database. EK, WVB, PC, TT, MD and HB added their expertise to the study design and methodology. 335